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1.
Nature ; 607(7917): 119-127, 2022 07.
Article in English | MEDLINE | ID: covidwho-1915276

ABSTRACT

The recent emergence of SARS-CoV-2 Omicron (B.1.1.529 lineage) variants possessing numerous mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies and antiviral drugs for COVID-19 against these variants1,2. The original Omicron lineage, BA.1, prevailed in many countries, but more recently, BA.2 has become dominant in at least 68 countries3. Here we evaluated the replicative ability and pathogenicity of authentic infectious BA.2 isolates in immunocompetent and human ACE2-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone4, we observed similar infectivity and pathogenicity in mice and hamsters for BA.2 and BA.1, and less pathogenicity compared with early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from individuals who had recovered from COVID-19 and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987 plus REGN10933, COV2-2196 plus COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir and S-217622) can restrict viral infection in the respiratory organs of BA.2-infected hamsters. These findings suggest that the replication and pathogenicity of BA.2 is similar to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron BA.2 variants.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , SARS-CoV-2 , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/pharmacology , Antibodies, Viral/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cricetinae , Cytidine/analogs & derivatives , Drug Combinations , Hydroxylamines , Indazoles , Lactams , Leucine , Mice , Nitriles , Proline , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Triazines , Triazoles
2.
Jpn J Infect Dis ; 2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1912148

ABSTRACT

Immunocompromised patients are more likely to develop severe COVID-19 and their mortality is high, while it is hypothesized that chronic infection in these patients can be a risk of developing new variants. We describe a patient with prolonged active infection of COVID-19 who became infected during treatment with anti-CD20 antibody (obinutuzumab) for follicular lymphoma. This patient had persistent RT-PCR positivity and live virus isolation for nine months despite treatment with remdesivir and other potential antiviral therapies. The computed tomography image of the chest showed that the viral pneumonia repeatedly appeared and disappeared in different lobes, as if new infection had occurred continuously. His antibody titer of SARS-CoV-2 was negative throughout the illness, even after two doses of BNT162b2 mRNA vaccine given in the seventh month. Combination of monoclonal antibody therapy against COVID-19 (casirivimab and imdevimab) and antivirals resulted in negative RT-PCR and the virus was no longer isolated. The patient was clinically cured. During the 9-month active infection, no fixed mutations in the S protein were detected and the in vitro susceptibility to remdesivir was retained. Therapeutic administration of anti-SARS-CoV-2 monoclonal antibodies is essential for immunocompromised patients. Measures to prevent resistance against these key drugs are in dire need.

3.
Viruses ; 14(5)2022 05 01.
Article in English | MEDLINE | ID: covidwho-1862910

ABSTRACT

Viral infections are influenced by various microorganisms in the environment surrounding the target tissue, and the correlation between the type and balance of commensal microbiota is the key to establishment of the infection and pathogenicity. Some commensal microorganisms are known to resist or promote viral infection, while others are involved in pathogenicity. It is also becoming evident that the profile of the commensal microbiota under normal conditions influences the progression of viral diseases. Thus, to understand the pathogenesis underlying viral infections, it is important to elucidate the interactions among viruses, target tissues, and the surrounding environment, including the commensal microbiota, which should have different relationships with each virus. In this review, we outline the role of microorganisms in viral infections. Particularly, we focus on gaining an in-depth understanding of the correlations among viral infections, target tissues, and the surrounding environment, including the commensal microbiota and the gut virome, and discussing the impact of changes in the microbiota (dysbiosis) on the pathological progression of viral infections.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Virus Diseases , Viruses , Dysbiosis , Humans
4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336969

ABSTRACT

ABSTRACT For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log 10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], −2.42 [1.42];P = 0.0712) and 250 mg (−2.81 [1.21];P = 0.0083) versus placebo (−1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by −1.4 to −1.5 log 10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).

5.
J Infect Chemother ; 28(7): 1015-1017, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1768315

ABSTRACT

By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , BNT162 Vaccine , COVID-19 Vaccines , Humans , RNA, Viral , Vaccines, Synthetic , mRNA Vaccines
6.
Microbiol Spectr ; 10(2): e0168921, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1731262

ABSTRACT

The role of the intestinal microbiota in coronavirus disease 2019 (COVID-19) is being elucidated. Here, we analyzed the temporal changes in microbiota composition and the correlation between inflammation biomarkers/cytokines and microbiota in hospitalized COVID-19 patients. We obtained stool specimens, blood samples, and patient records from 22 hospitalized COVID-19 patients and performed 16S rRNA metagenomic analysis of stool samples over the course of disease onset compared to 40 healthy individual stool samples. We analyzed the correlation between the changes in the gut microbiota and plasma proinflammatory cytokine levels. Immediately after admission, differences in the gut microbiota were observed between COVID-19 patients and healthy subjects, mainly including enrichment of the classes Bacilli and Coriobacteriia and decrease in abundance of the class Clostridia. The bacterial profile continued to change throughout the hospitalization, with a decrease in short-chain fatty acid-producing bacteria including Faecalibacterium and an increase in the facultatively anaerobic bacteria Escherichia-Shigella. A consistent increase in Eggerthella belonging to the class Coriobacteriia was observed. The abundance of the class Clostridia was inversely correlated with interferon-γ level and that of the phylum Actinobacteria, which was enriched in COVID-19, and was positively correlated with gp130/sIL-6Rb levels. Dysbiosis was continued even after 21 days from onset. The intestines tended to be an aerobic environment in hospitalized COVID-19 patients. Because the composition of the gut microbiota correlates with the levels of proinflammatory cytokines, this finding emphasizes the need to understand how pathology is related to the temporal changes in the specific gut microbiota observed in COVID-19 patients. IMPORTANCE There is growing evidence that the commensal microbiota of the gastrointestinal and respiratory tracts regulates local and systemic inflammation (gut-lung axis). COVID-19 is primarily a respiratory disease, but the involvement of microbiota changes in the pathogenesis of this disease remains unclear. The composition of the gut microbiota of patients with COVID-19 changed over time during hospitalization, and the intestines tended to be an aerobic environment in hospitalized COVID-19 patients. These changes in gut microbiota may induce increased intestinal permeability, called leaky gut, allowing bacteria and toxins to enter the circulatory system and further aggravate the systemic inflammatory response. Since gut microbiota composition correlates with levels of proinflammatory cytokines, this finding highlights the need to understand how pathology relates to the gut environment, including the temporal changes in specific gut microbiota observed in COVID-19 patients.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Bacteria/genetics , Cytokines , Dysbiosis/microbiology , Feces/microbiology , Gastrointestinal Microbiome/physiology , Hospitalization , Humans , Inflammation , RNA, Ribosomal, 16S/genetics
8.
iScience ; 25(2): 103830, 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1654627

ABSTRACT

CRISPR-based diagnostics (CRISPR-dx), including the Cas12-based DETECTR and Cas13-based SHERLOCK Class 2 CRISPRs, have been used to detect the presence of DNA or RNA from pathogens, such as the 2009 pandemic influenza virus A (IAV) and the 2019 novel coronavirus SARS-CoV-2. Here, we describe the collateral single-stranded DNA cleavage with Class 1 type I CRISPR-Cas3 and highlight its potential for development as a Cas3-mediated rapid (within 40 min), low-cost, instrument-free detection method for SARS-CoV-2. This assay, which we call Cas3-Operated Nucleic Acid detectioN (CONAN), not only detects SARS-CoV-2 in clinical samples, but also offers specific detection of single-base-pair mutations in IAV variants. This tool allows rapid and accurate point-of-care testing for patients with suspected SARS-CoV-2 or drug-resistant IAV infections in hospitals.

12.
EClinicalMedicine ; 32: 100734, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1385450

ABSTRACT

BACKGROUND: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients. METHODS: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay. FINDINGS: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort. INTERPRETATION: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection. FUNDING: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.

13.
PLoS One ; 16(6): e0253293, 2021.
Article in English | MEDLINE | ID: covidwho-1280625

ABSTRACT

BACKGROUND: Human microbiotas are communities of microorganisms living in symbiosis with humans. They play an important role in the host immune response to respiratory viral infection. However, evidence on the human microbiome and coronavirus disease (COVID-19) relationship is insufficient. The aim of this systematic literature review was to evaluate existing evidence on the association between the microbiome and COVID-19 in humans and summarize these data in the pandemic era. METHODS: We conducted a systematic literature review on the association between the microbiome and COVID-19 in humans by searching PubMed, Embase, and the Cochrane Library, CINAHL, and Web of Science databases for articles in English published up to October 31, 2020. The results were analyzed qualitatively. This study is registered with PROSPERO (CRD42020195982). RESULTS: Of the 543 articles identified by searching databases, 16 in line with the research objectives were eligible for qualitative review: eight sampled the microbiome using stool, four using nasopharyngeal or throat swab, three using bronchoalveolar lavage fluid, and one using lung tissue. Fecal microbiome dysbiosis and increased opportunistic pathogens were reported in COVID-19 patients. Several studies suggested the dysbiosis in the lung microbiome of COVID-19 patients with an abundance of opportunistic pathogens using lower respiratory tract samples. The association between COVID-19 severity and the human microbiome remains uncertain. CONCLUSION: The human fecal and respiratory tract microbiome changed in COVID-19 patients with opportunistic pathogen abundance. Further research to elucidate the effect of alternation of the human microbiome in disease pathogenesis is warranted.


Subject(s)
COVID-19/microbiology , Dysbiosis/microbiology , Microbiota , Nasopharynx/microbiology , Bronchoalveolar Lavage Fluid , Dysbiosis/virology , Feces/microbiology , Gastrointestinal Microbiome , Humans
14.
JMA J ; 4(2): 148-162, 2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1226034

ABSTRACT

In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.

15.
HLA ; 98(1): 37-42, 2021 07.
Article in English | MEDLINE | ID: covidwho-1199730

ABSTRACT

HLA-A, -C, -B, and -DRB1 genotypes were analyzed in 178 Japanese COVID-19 patients to investigate the association of HLA with severe COVID-19. Analysis of 32 common HLA alleles at four loci revealed a significant association between HLA-DRB1*09:01 and severe COVID-19 (odds ratio [OR], 3.62; 95% CI, 1.57-8.35; p = 0.00251 [permutation p value = 0.0418]) when age, sex, and other common HLA alleles at the DRB1 locus were adjusted. The DRB1*09:01 allele was more significantly associated with risk for severe COVID-19 compared to preexisting medical conditions such as hypertension, diabetes, and cardiovascular diseases. These results indicate a potential role for HLA in predisposition to severe COVID-19.


Subject(s)
COVID-19 , HLA-DRB1 Chains , Alleles , COVID-19/diagnosis , COVID-19/genetics , Gene Frequency , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Humans
17.
Sci Adv ; 7(10)2021 03.
Article in English | MEDLINE | ID: covidwho-1119272

ABSTRACT

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.


Subject(s)
Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigens, Viral/immunology , Biomarkers/blood , COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Antibody Affinity/immunology , Antibody Formation/immunology , COVID-19/blood , COVID-19/virology , Cytokines/blood , HEK293 Cells , Hospitalization , Humans , Immunoglobulin Class Switching , Kinetics , Neutralization Tests , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Load
19.
Viruses ; 12(12)2020 12 10.
Article in English | MEDLINE | ID: covidwho-970091

ABSTRACT

Reverse transcription-quantitative PCR (RT-qPCR)-based tests are widely used to diagnose coronavirus disease 2019 (COVID-19). As a result that these tests cannot be done in local clinics where RT-qPCR testing capability is lacking, rapid antigen tests (RATs) for COVID-19 based on lateral flow immunoassays are used for rapid diagnosis. However, their sensitivity compared with each other and with RT-qPCR and infectious virus isolation has not been examined. Here, we compared the sensitivity among four RATs by using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates and several types of COVID-19 patient specimens and compared their sensitivity with that of RT-qPCR and infectious virus isolation. Although the RATs read the samples containing large amounts of virus as positive, even the most sensitive RAT read the samples containing small amounts of virus as negative. Moreover, all RATs tested failed to detect viral antigens in several specimens from which the virus was isolated. The current RATs will likely miss some COVID-19 patients who are shedding infectious SARS-CoV-2.


Subject(s)
Antigens, Viral/analysis , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Point-of-Care Systems , SARS-CoV-2/isolation & purification , False Negative Reactions , Humans , Immunoassay , Real-Time Polymerase Chain Reaction , SARS-CoV-2/immunology , Sensitivity and Specificity , Specimen Handling
20.
Hepatol Res ; 51(2): 227-232, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-852324

ABSTRACT

AIM: Liver dysfunction is sometimes observed in patients with coronavirus disease 2019 (COVID-19), but most studies are from China, and the frequency in other countries is unclear. In addition, previous studies suggested several mechanisms of liver damage, but precise or additional mechanisms are not clearly elucidated. Therefore, we examined COVID-19 patients to explore the proportion of patients with liver dysfunction and also the factors associated with liver dysfunction. METHODS: We retrospectively examined 60 COVID-19 patients hospitalized at the Hospital affiliated with The Institute of Medical Science, The University of Tokyo (Tokyo, Japan). Patients who presented ≥40 U/L alanine aminotransferase (ALT) levels at least once during their hospitalization were defined as high-ALT patients, and the others as normal-ALT patients. The worst values of physical and laboratory findings during hospitalization for each patient were extracted for the analyses. Univariable and multivariable logistic regression models with bootstrap (for 1000 times) were carried out. RESULTS: Among 60 patients, there were 31 (52%) high-ALT patients. The high-ALT patients were obese, and had significantly higher levels of D-dimer and fibrin/fibrinogen degradation products, as well as white blood cell count, and levels of C-reactive protein, ferritin, and fibrinogen. Multivariable analysis showed D-dimer and white blood cells as independent factors. CONCLUSIONS: Considering that higher D-dimer level and white blood cell count were independently associated with ALT elevation, liver dysfunction in COVID-19 patients might be induced by microvascular thrombosis in addition to systemic inflammation.

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